We have examined whether ventral forebrain dopamine projection areas were activated prior to motor behavior, during anticipation of reward and punishment. During the anticipation interval, subjects saw a cue indicating that they could either win money or not, waited a variable delay, and then pressed a button in response presentation of a target. If subjects responded before the target following the reward cue disappeared, they won $5.00, $1.00, or $.20 whereas their response to the neutral target did not affect their total. During the active avoidance portion of the task, subjects responded to targets that followed either a punishment cue or a neutral cue. If they failed to respond before the disappearance of the target following the punishment cue, they lost $5.00, $1.00, or $.20 whereas their response to the neutral target again did not affect their total. T2*-weighted gradient echoplanar MR volumes depicting blood oxygenation level dependent (BOLD)-contrast were acquired using a 3.0 Tesla GE System. After correcting for in-plane motion, individual voxel activations were correlated with an ideal waveform corresponding to the expected activation time course using the AFNI software package. The ideal waveform consisted of a waveform representing the task that was convolved with the brain hemodynamic response function. Anticipation of reward activated striatal areas (caudate, putamen) and mesial forebrain areas (anterior cingulate, mesial prefrontal cortex, and thalamic regions). Anticipation of punishment also activated these regions relative to anticipation of no monetary outcome. However, anticipation of reward but not punishment produced activation in the nucleus accumbens. Magnitude of nucleus accumbens activation predicted the amount of positive emotion subjects reported feeling when the cues signaling monetary reward. We also separately examined reward anticipation and outcomes with event-related fMRI. This study confirmed that the nucleus accumbens is recruited by anticipation of monetary reward. Studies are currently ongoing to compare the brain response to anticipation of working to gain reward or to avoid punishment in adolescents with and without a family history of alcoholism or substance abuse. These studies have shown that healthy adolescents without a family history of alcoholism activate the same brain circuit during anticipation of working for reward as adults do, but that the magnitude of the activation is less than the magnitude seen in adults. Results from this work suggest that alcoholics studied three weeks from their last drink show a slightly blunted response in the nucleus accumbens compared to non-alcoholics when they anticipated working for reward, We have also developed a series of fMRI tasks which allow us to examine brain BOLD response during a risk taking task in which financial reward is determined by how much risk an individual is willing to endure. This task shows robust BOLD activation in the cognitive division of the anterior cingulate cortex, and that this activation is less pronounced among adolescents. This may represent a brain correlate of the developmental tendency of adolescents to engage in risky behavior. Studies are also underway to examine the relationship between the magnitude of voluntary effort required to complete a task, uncertainity of reward and the magnitude of BOLD activation in the ventral striatum. During fMRI, subjects saw cues signaling probabilities of 1.0, 0.5, and 0 of winning $1 for hitting a subsequent target, and cues signaling similar probabilities of reward delivery requiring no instrumental response. Non-instrumental reward anticipation did not elicit activation. Instrumental reward anticipation activated multiple nodes of the basal ganglia-thalamocortical motor circuit. Ventro-mesial striatum was activated by joint requirement for an instrumental response together with uncertain (but not certain) reward. Using the an advanced version of the motivational task described above which allows us to more clearly separate individual events during a sequence of motivated behavior, we have recently shown that alcoholics are more sensitive to the notification of both rewarding or punishing outcomes than non-alcoholic controls. This increased sensitivity to outcome is present in both the ventral striatum and the anterior insular cortex and may relate to differences in impulsivity that characterize substance-abusing individuals. In addition, it is possible that this increase sensitivity to outcome maybe equivalent to a greater magnitude of prediction error among alcoholics. Prediction error is a major component of models of human, animal and machine learning. Prediction error has been shown to correspond to the activity of midbrain dopamine neurons and BOLD activation in the nucleus accumbens. The effect of pharmacological probes such as amphetamine, dopamine depletion and intravenously administered ethanol are also being investigated. Intravenously administered ethanol is associated with a significant increase in BOLD signal in the ventral forebrain, including extended amygdala nucleus accumbens. We have also used an event-related fMRI approach to examine alcoholics BOLD response during their evaluation of emotional stimuli and to compare their response to that of non-alcoholic controls. The task used was a simplified variant of a facial emotion-decoding task in which subjects determined the intensity level of a target emotion displayed as a facial expression. Facial expressions of happy, sad, anger, disgust and fear were used as stimuli. Alcoholics and controls did not differ in the accuracy with which they identified the intensity level during the simple emotional decoding task but there were significant differences in their BOLD response during evaluation of facial emotion. In general, alcoholics showed less brain activation than non-alcoholic controls. The greatest differences in activation were during decoding of facial expressions of fear and disgust during which alcoholics had significantly less activation than controls in the affective division of the anterior cingulate cortex (ACC). Alcoholics also had significantly less activation than controls in the affective division of the ACC while viewing sad faces. These results suggest that alcoholics show a deficit in the function of the affective division of the ACC during evaluation of negative facial emotions that can serve as cues for flight or avoidance. This deficit may underlie some of the behavioral dysfunction in alcoholism. We have recently begun a study to examine a very simple executive brain function among alcoholics. Results from other functional imaging labs have suggested that alcoholics show greater activation than non-alcoholics in circuits involving frontal lobes when engaged in executive-type tasks. We compared brain activations of alcohol dependent patients and healthy non-alcoholics while they performed two simple judgment tasks designed to activate frontal circuits involved in a basic form of decision making. Participants completed one judgment task that required an emotional judgment and one task that did not. This study will enabled us to determine whether alcoholics have greater brain activation while performing executive tasks as well as to determine if emotional tasks elicited even greater activation than non-emotional tasks.